SYNTHESIS AND REACTIONS OF CERTAIN BENZOTHIAZOLES1~ 2

The observation that 2-methoxy-8-(3-diethylaminopropylamino)quinoline (I) ...... (16) WHEELER AXD BARSES, Ani. Chern. J., 24, 71 (1900); 22, 141 (lS99...
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SYNTHESIS AND REACTIONS O F CERTAIN BENZOTHIAZOLES1~ 2 ROBERT

C.E L D E R F I E L D

AND

FRANKLIN Pi. SHORT'

Received February 18, 1963

The observation that 2-methoxy-8-(3-diethylaminopropylamino)quinoline(I) exerts a definite effect on the development and course of poliomyelitis (1) in monkeys prompted an investigation of analogous compounds. I, despite its definite effect on the disease, was too toxic to be of practical use (1). Replacement of the cliethylamino group of I by a primary amino group (2) provided a substance of greatly decreased toxicity (3) but devoid of effect on poliomyelitis (1). It therefore seemed of interest to investigate the action of the S-isoster of 1, namely 2-methoxy-4- (3-diethylaminopropylamino) benzothiazole (11). A report describing the results of an exploration of one synthetic approach to I1 has already appeared (4). In the present paper we wish to report our further experience on the attempted synthesis of 11. Although preparation of I1 has not been achieved, certain observations on the synthesis and reactions of benzothiazoles have been made which may be of interest. The logical approach to TI involves alkylation of 2-methoxy-4-aminobenzothiazole (111) by 3-diethylaminopropyl chloride. I11 thus becomes the key intermediate in the synthesis of the candidate drug and efforts have been directed towards its preparation or towards the preparation of 2-methoxy-4-nitrobenzothiazole (IV). o-Nitrophenyl isothiocyanate (V) wis prepared in good yield from o-nitroaniline and thiophosgene by a modification of the general procedure of Dyson and George ( 5 , 6). Reaction of V with alcoholic ammonia gave o-nitrophenylthiourea {VI) ( 5 , 7, S> although the yield was disappointingly low. Oxidative ring closure of VI with bromine (7) gave 2-amino-4-nitrobenzothiazole (VII) in good yield. However all attempts to convert VI1 to 2-chloro-4-nitrobenzothiazole (VIII) failed. The complete resistance of VI1 to diazotization was unexpected although there are reports of failure to diazotize 2-aminobenzothiazoles (9). On the other hand several reports of the successful diazotization of these compounds are a t hand (10). 1 We wish to acknowledge s grant from the Sational Foundation for Infantile Paralysis through the Children's Hospital, Cincinnati Ohio, which supported in part tho investigation here reported. e The work here reported forms part of n dissertation submitted by Franklin N'. Short, in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Colunibia University. Present address : Department of Chemistry, University of Michigan, Ann Arbor, MiCh. * Union Carbide and Carbon Fellow i n Columbia University 1951-1952. J

1092

SYKTHESIS O F CERTAIN BENZOTHIBXOLES

1093

Attention was then turned to the possibility of obtaining IV by the general method (11):

nl

‘

/‘UHCR

\/- /)

____)

NaOH Ha0

S IX.

It has been reported that this synthesis proceeds in good yield when R is methyl and R’ is p-methoxy, p-methyl, or p-chloro, whereas when these substituents are in the ortho position of IX or a nitro group is in the para position of IX the yields of benzothiazoles are poor (12). Jacobson and Klein (13) report that p-nitrophenylthionurethan (IX, R = OC2H6, R’ = p-NOs) gave p-nitrophenylurethan with cold alkaline ferricyanide. Oxidation of IX (R = OCHs, R’ = 0-h-02) gave only o-nitroaniline and unreacted starting material. Thus the above generalization may be extended to include the effect of a cationoid ortho nitro group which completely inhibits ring closure. The effect of bromine on compounds of the type of IX in which R is a group other than amino has not been investigated as thoroughly. I n certain cases bromine in acetic acid oxidizes these to bensothiazoles in good yield (14). When IX (E = OCHB,R’ = 0-1;02) was treated with bromine in acetic acid or chloroform a t room temperature an exothermic reaction ensued and an isomeric product to which the structure of the rearranged substance, methyl o-nitrophenylthiolcarbamate (X), is assigned was formed. This proposal is supported

KO2

by conversion of X to o-nitroaniline by cold 5 % aqueous sodium hydroxide and to o-nitrophenylurea by cold concentrated ammonium hydroxide. Will (15) noted

1894

R. C. ELDERFIELD AND F. '8. SHORT

that the related methyl phenylthiolcarbamate undergoes the same reactions to give aniline and phenylurea. An analogy for this rearrangement is found in the reported (16) conversion of methyl phenylthioncarbamate (XI) to XI1 by the action of methyl iodide at room temperature. Several thioncarbamic, thioncarbanilic, and thioraearbneinic

XI.

XEI.

esters have been observed to undergo this rearrangement when heated with alkylhalides. However, the present case apparently represents the first broinineinduced rearrangement of this type. Likewise, similar rearrangements have been induced thermally (1'7). In view of the report that the chlorine in 8-chloroquinoline k activated towards nucleophilic reageiits especially in the presence of copper (IS), the (XIII) with 3-diethylaminopropylreaction of 2-methoxy-4-chlorobenzothiaeole amines was investigated although it was realized that the methoxyl group of XI11 might also undergo aminolysis. 2-Amino-4-chlorobenzothiazole (19) was converted in good yield to 2-bromo-4-chlorobensothiazole (XIV) by Craig's procedure for the preparation of 2-bromopyridine (20). The yield by this procedure is fer better than those previously reported by diazotization of the weakly basic -S

_ HNOI _I)

HBr

C1

o-8, o-' ------+ CRiONa

\

\

\?\'@.

I \M- bcrr,

c1

c1

XIV.

XIII.

/

(c~EI~)~N(cH~)~NH~/ I(

C1

XV.

2-aminobeneothiazolefi. Reaction of XIV with sodium methoxide gave XI11 which was heated with 3-diethylaminopropylaminealone and in the preeence of anhydrous cupric chloride or anhydrous sodium acetate. Only with sodium acetate at 180-200O was there obtained a very low yield of a substance the analytical data for which indicated the structure XV. All of the methods explored for the preparation of I11 failed because of the 6 For a review of t h e methods for replacement of aromatic halogens with amines see Bennett and Zahler, Chem. Revs., 49, 281 (1961).

SYNTHESIS OF CERTAIN BENZOTHIAXOLES

1095

presence of the deactivating 4-nitro group. An alternative scheme involves introduction of the nitro group into the $-position after the necessary functional group (methoxyl or a group readily convertible to methoxyl) had been placed at the 2-position. The literature on electrophilic substitution reactions of benzothiasole and its Bz-substit#u.kedderivatives is fairly confused. Pullman and Metsger (21) have calculated the electron distribution about benzothiazole and 2-methylbensothiazole by the molecular orbital method. From their calculations electrophilic substitution should occur predominantly a t the 4- and/or 6-positions. Experimentally it has been observed that halogenation, nitration, and sulfonation of benzothiazoles unsubstituted in the benzene ring give the &substituted derivatives either exclusively or very nearly so (22-29). Nishizawa and co-workers (25) report that nitration of benzothiazole a t 0" gave, in addition to G-nitrobenzohihiasole, a small amount of the '?-nitro isomer (m.p. 138"). Petitcolas, et al. (24) also obtained an isomer, m.p. 135", which they believed to be 4-nitrobenzothiazole. Hunter and eo-workers (30) observed that certain benzothiazoles already substituted in the 6-position (XVI) gave the 4-bromo derivative on bromination in chloroform.

XVI

R = Br, C1, CHz R' = H, CHI

A different orientation has been noted with 6-aminobenzothiazole. Boggust and Cocker (26) found that this substance on bromination in chloroform gave the 7-bromo derivative whereas in the presence of sodium acetate an isomer which they believed to be the 5-bromo derivative was produced. When the bromination was done in acetic acid a mixture of the two isomers was obtained. Similarly, bromination of 2-hydroxy-6-methylbenzothiazolegave a product which was shown to be either the 5- or 7-bromo derivative (31). Fries and Buckler (32) observed that 6-hydroxy-2-phenylbenxothiazolegave the 7-chloro derivative on chlorination, but that bromination led to the 5-bromo derivative. Nitration of the same substance gave a mixture of the 5- and 7-nitro derivatives with the latter predominating. Fox and Bogert (33) on the other hand isolat,ed only the 7-nitro compound from the same reaction and also from the product's of nitration of 6-methoxy- and 6-methoxy-2-phenyl-benzothiazole.Sulfonation of 2-amino-6-methylbenzothiazole gave the 5-sulfonic acid, whereas sulfonation of 2,6-dimethyl- and 6-methyl-2-phenyl-benzothiazole gave the 7-sulfonic acid (34). We have found no report of the nitration of a benzothiazole carrying a weakly

1096

R. C. ELDERFIELD AND F. W. SHORT

ortho, para-directing bromine or chlorine a t the 6-position as the only substituent in the benzene ring. In view of the orientation noted by Hunter, et al. (22, 30) in the bromination of 6-bromobenaothiaaoles (further substitution at the 4position) it seemed reasonable to expect that nitration of such a substance would lead to a 4-nitro derit-atir-e from which the bromine can subsequently be removed. Accordingly the reactions outlined below were investigated :

xxr.

XIX.

XIV.

XXIV.

Kitration of 2 I 6-dibromobenzothiaeole (XVII) with potassium nitrate and sulfuric acid (28) gave a mixture of the three possible isomers in quantitative yield. By recrystallization from alcohol 71 % of a mono-nitro compound, map. 142-143", which is assigned the structure of 2,6-dibromo-7-nitrobenzothiasole

1097

SYNTHESIS O F CERTAIN BEKZOTHIALOLEB

(XVIII) for reasons given below, was obtained. On concentration of the mother liquors from XVIII a mixture of the other two isomers was obtained. Extraction with boiling methanol gave a methanol-soluble substance, m.p. 125-126', and a methanol-insoluble substance, m.p. 176-178'. The major product (XVIII) was converted to 6-bromo-2-rnethoxy-7-nitrobenzothiazole (XIX) by sodium methoxide in pyridine-methanol. A considerable (XX) was also formed preamount of 6-bromo-2-hydroxy-7-nitrobenzothiazole sumably as a result of an incomplete exclusion of moisture. XX also resulted from the action of 5 % sodium hydroxide on XVIII. Considerable difficulty was encountered in the reduction of XIX to 7-amino-2methoxybenzothiazole (XXII). When the reduction was carried out in methanol or ethanol over palladium on calcium carbonate (35) a t room temperature and 3-4 atmospheres of hydrogen only 7-amino-6-bromo-2-methoxybenzothiazole (XXI) was obtained. However when the reduction was carried out in the presence of sodium acetate as a hydrogen ion acceptor, XXII was obtained. TABLE

MELTIW POIKTS OF

THE

I BENZOTHIAZOLBS

BESZOTHIAZOLE

5-Amino-2-methoxy (36). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T-Aniino-2-methoxy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-Chloro-2-hydroxy (37). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7-Chloro-2-hydroxy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I

X.P., "C.

171-172 73-75 230-231 203-205

The amino group in X X I I was converted t o chlorine by the Sandmeyer reaction during which the methoxyl group was also cleaved to give 7-chloro-2-hydroxybenzothiazole (XXIII) , m.p. 203-205'. An authentic sample of 4-chloro-2-hydroxybenzothiazole(;riXITi) was prepared by reaction of the previously described 2-bromo-4-chlorobenzothiazole (XIV) wit,h 5 70 sodium hydroxide solution. This melted at 202-203'. However a mixture melting point of XXIV and XXIII was 183-167'. Therefore the major product of the nitration of XVII was not the desired 6-bromo-4-nitrobenzothiazole, but rather either the 5- or 7-nitro derivative. A rigorous proof of the structure of XVIII is complicated by the fact that unambiguous methods have not been devised for the ready synthesis of 7-substituted benzothiazoles and by the difficulty of degrading XVIII or the benzothiazoles derived from it to derivatives which may be readily synthesized for comparison. Ho-ivever, 5-amino-2-methoxy- (36) and 5-chloro-2-hydroxy-benzothiazole (37) have been described. It should be pointed out that the structure assigned to 5-amino-2-methoxybenzothiazoleis open to question. The methyl group was introduced by methylation of the 2-hydroxy derivatiw with dimethyl sulfate in alkaline solution. Experience (31, 38) indicates that under these conditions the N-methyl derivative is to be expected. However the structures of the 5- and 7-chloro-2-hydroxybenzothiazolesappear to rest on firm ground. On the

1098

R. C. ELDERFIELD AND F. W-. SNORT

basis of the differencesof melting points for these substances and those observed for XXII and XXIII as shown in Table I we have assigned to our beneothiaeoles the 7-substituited structures. GXPFRIMEKTAL~ 7

o-Sitrophenyl isolhiocyannle (I-).This was preparcd by a inodificntion of t h e general niethod of Dyson (5, 6). A solution of 25 g. (0.18 mole) of o-nitroaniline in 500 ml. of hot 2CWo hydrochloric acid was placed in i i three-necked flask equipped wit11 a stirrer, reflux condenser, and thermometer (hood). After cooling the mixture t o 50", 10 ml. (15 g., 0.13 mole) of thiophosgene (Itapter Laboratories, Argo, Ill.) was added in one portion. Stirring was started and the ternpernture of the mixture was maintained a t 45-50"for 4 hours during which period a yellow solid precipitated. The mixture was stirred a t room temperature for ttn additional 18 hours. Recrystaliiaittion of the crude produrt by solution in 200 ml. of hot :rcerone and dilution with 50 ml. of water gave 20.1 g. (86%) of product aa yellow needles, m.p. 75-76". Condensatioii of o-nitroaniline witli thiophosgene in chloroform according t o Erlenmeycr and Ueberwasser (7b) g!Lve low yields of extremely impure product. o-Nitrophenyltlaioureu (VI,. After considerable experimentation the following modification of published methods ( 5 , 71 gave the most consistent results. T o a solution of 45.5 g (0.25 mole) of V in 450 nil. of warm 55% ethanol which had been cooled slowly t o 36" was added 225 ml. of conc'd ammonium hydroxide in one portion with stirring. After standing at room temperature x i t h occasional shaking for one hour, t h e dark red solution was diluted t o 2 1. and refrigerated for 3 days. The thiourea, m.p. 136-137", crystallized as fine yellow needles or glistening platelets. The yield was 26.6 g. (53.5%). An attempt t o prepare VI from impure Y prepared by the method of Erlenmeyer and Ueberirssser (7b) resulted only in the formation of o-nitrophenglcyanamide, m.p. 152IS", [reported 152" (3'J)] which was identified by hydrolysis t o o-nitrophenylurea, m.p, 183-184" [reported 183-184' (39)l. R-ditiiiao-4-~~~troben%othiazole (VIX), m.p. %So, was obtained in 98% yield by oxidative ring closure of V I by bromine in chloroform (7). Jfethy2 o-nilrophany~thioncurb~mats (IX, R = OCHs, R' = o-Xo2). -4 solution of 2 g. (0.01 mole) of o-nitrophenyl isothiocyanate in 10 ml. of dry methanol was heated under reflux for 17 hrs. (13, 16, 31). On cooling 0.7 g. of yellow crystals separatcd and dilution of the mother liquor gave an additional 1.5 g. The total yield w-as 93%. On recrystallization from methanol, the substance formed yellow rsods, m.p. 67-68'. A n a l . Calc'd for C8H3Kp0&4:C, 45.3; H, 3.8; N , 13.2; S, 15.1. Found: C, 45.3;H, 3.9; N , 13.1; S , 15.3. When the reaction time was decreased to 6 hours the yield dropped t o 727,. When 1 g. of t h e isothiocyanate was allowed t o stand in a solution of 1 g. of potassium hydroxide in 10 ml. of methanol for 65 hours (40) t h e yield was 63.5%. ,Ifethyl o-nit,ophen~lthiolcai~bamate (S). A solution of 1.52 g. (0.0095 mole) of bromine in 5 1111.of glacial acetic acid was added dropwise with cooling t o a solution of 2.0 g. (0.0094 mole) of methyl o-nitrophenylthionrarbamate i n 10 ml. of glacial acetic acid during which period D thick finely crystalline precipitate separated. Bn additional 10 ml. of acetic acid \vas added. After4 hours the precipitate was collectedttnd washed with a few ml. of methanol yielding 1.50 g. (75%) of X, m.p. 152-153" (dec.). Recrystallization from benzene gave light 3 ellow platelets, m.p. 153.5-154" (dec.). A n a l . Found: C, 45.0; H, 3.7; N,13.3; S, 15.4. R h e n t h e above reaction was run in acetic acid without addition of bromine only starting material was recovered.

* All melting points are corrected for stern exposure. 7 Microanalyses by Schwarzkopf Microanalytical Laboratories, Middle Village, L . X , Y . ; Dr. A. Elek, Los Angeles, Cal.; or Micro-tech Laboratories, Skokie, Ill.

I.,

BTNTHESIS O F CERTAIN BENZOTHIbZOLES

1099

When the reaction was run it1 dry chloroform with broininc for 18 hours a l o n w yield of less easily purified S was obtained. X is soluble i n cold 5% aqueous sodium hydroxide solution. On acidification of this orange solution a mercaptan-like odor was apparent and 2-nitroaniline, n1.p. and mixture m.p., 69.71" after recrystallization from water, separated. When X was treated n-ith cold conc'd ammonium hydroxide i t was converted t o onitrophenylurea, ni.p. and mixture m.p. 183-185" after recrystallization from water containing a little ethxiiol. Acidification of the ammoniacal filtrate gave a mercaptan-like odor. o-Chlol.ophonylthiozL1.ea. T h e present procedure is siniiiar t o but considerably simpler than t h a t previously reported (41). A hot solution of 44.6 g. (0.35 mole) of freshly distilled o-chloroaniline in 32.5 ml. (0.38 mole) of eonc'd hydrochloric acid and 175 nil. of water was added t o a solution of 56.0 g. (0.735 mole) of ammonium thiocyanate in 12UO ml. of water in a flask equipped with a sealed stirrer and reflux condenser. The mixture was stirred and heated under reflux for 6 hours. After cooling f o r 18 hours during which period the solid product precipitated, the aqueous slurry was decanted from a heavy oil, and 18.0 g. (27.6%) of t h e thiourea, m.p. 142-143', was collected. Recrystallization froin benzene gave glistening white plat,es, m.p. 143.5-144.5". Reported m.p. 144-146" (41) and 145' (19). A n alternate procedure, a modification of t h a t of Dalgleish and Mann (42) was also used To a solution of 329 g. (2.5 moles) of o-chloroaniline in 1750 nil. of chlorobenzene (600 ml. of which was saturated from a previous run) 135 g. (1.3 moles) of conc'd s-ilfuric acid was added dropwise with stirring over 5 min. After addition of 225 g. (2.78 moles) of sodium thiocyanate t h e mixture was heated under reflux at 100' for 5 hours and then allowed t o stand a t room temperature for 18 hours. T h e solvent was poured off and the solid residue was mashed with ether, by decantation and dried. The crude product was stirred with 6% ml. of water for 30 niin., collected, and dried, giving 239 g. (51.3%) of material, m.p. 140142'. The yield froin smaller runs in which the reaction time was only 3 hours and fresh solvent was used was only 40'%. Z-Bro,izo-/t-chlorobenzofkiazo/e (XIV). (20).2-~4mino-4-chlorobenzothiazole, n1.p. 208209' [reported 203" (lSa)], was prepared in 72.3% yield (7, 19b). T o 125 ml. (1.1 moles) of 48% hydrobromic acid chilled to lo', 46.2 g. (0.25 mole) of 2-amino-4-chlorobeneothia9ole was added slowly with stirring. After cooling the mixture to 0" t o -5", 39 ml. (0.76 mole) of bromine was added dropwise followed by a solution of 45.5 g . (0.625 mole) of sodiuin nitrite in 65 nil. of water. The temperature rose t o 5" toward the end of the addition of the nitrite. The dark viscous mixture was stirred in the cooling bath for 2 hours and then made alkdine by dropwise addition of at solution of 94 g. (2.35 moles) of sodiuin hydrovide in 94 ml. of water during which time tho temperature was maintained below 20". After 20 min. the dark solid was collected, washed with water, air-dried, and extracted with several portions of boiling 95% ethanol. After treatment with decolorizing carbon, the cooled extracts yielded 44.9 g. (72.3%) of XIV as yellow needles, m.p. 107-108". Anal. Calc'd for GHsBrCINS: C, 33.8; H, 1.2; R r , 32.1; C1, 14.3; N , 5.6; 8 , 12.1). Found: C, 34.0; 13, 1.4; Br, 31.9; C1,14.3; N, 5.8; S, 12.7. When the reaction was allowed t o run only 30 min. before addition of sodium hydroxide, the yield of X I V , n1.p. 105-106" u a s only 47.5%. 6-ChZoPo-~-nzethosyhenzothiazolB(3311). 2-Bromo-4-chlorobenxotliiazole (4.98 g., 0.02 mole) w m added to a solution of sodium methoxide prepared from 0.48 g. (0.02 mole) of sodiuni and 8 ml. of absolute methanol. After boiling under reflux for 2 hours, the mixture was poured into 50 nil. of water. The granular precipitate was washed with water and dried t o yield 3.8 g. (95%) of XIIE, m.p. 56-58". After recrystallization from methanol with carbon the substance formed hard white plates, m.p. 57-59'. Anal. Cdc'd for CsH&lNOS: C, 48.1; H, 3.0; C1, 17.8; N , 7.0; S, 16.1. Found: C, 48.4; 11, 3.3; C1, 17.7; N , 7.1; S, 16.0. .i-Ch2o~o-tZ-(9-diethylnlnd~~opropy2amino)beoizothiazole (XV). A mixture of 5.0 g. (0,025 mole) of X I I I , 3.25 g. (0.026 inole) of 3-diethylan~inopropylami1~e, and 4.1 g. (0.06 mole) of anhydrous fiodium acetate \%asheated under reflux in an oil bath at 180-200" (bath tem-

1100

R. C. ELDERFIELD &4XD F. W. SHORT

perature) for 11 hours. The cooled semi-solid mass n a s treated with 100 ml. of water and extracted with 3 portions of ether. The combined ether extracts were vashed with water until the washings were nearly neutral and were dried over potassium carbonabe. The oily residue after removal of the ether, (1.4 g.), wa8 taken up in ethyl acetate and filtered from a small amount of insoluble material. A solution of oxalic acid in ethyl acetate was added t o the filtrate until precipitation was complete. After addition of ethanol t o dissolve tho oily salt, the filtered solution was taken t o dryness. Trituration of the residue with ethyl acetate gave 0.3 g. of a light tan powder vt-hich formed platelets, m.p. 173-175" (dec.), after t w o recrystallizations from ethanol-ethyl acetate. Anal. Calc'd for C16H2X1S304S:C , 49.5; H, 5.7; Cl, 9.1; 0, 16.5; (COOI-I)2,23.21. Found: 6,N.O;H, 5.7; C1,S.i; 0, 13.1; (COOR)z,19.5. Although the product was not analvtically pure, the analytical data indicated t h a t reaction had orcurred a t position 2 rather than a t position 4. W,6-Dibromoben201h~azo2e (XVII) . This ~ a prepared s from 2-amino-6-brornobenzothiazole [prepared by thiocyanation of p-bromoaniline in acetic acid (43,44)]by the procedure used for the preparation of 2-bromo-4-chlorobenzotliiazole. The yield of crude material, m.p. 109-114" was 78.5%. Two recrystallizations from ethanol gave fine white needles, m.p. 119-121". Anal. Calc'd for CiI&UrzSS: C, 28.7; 13, 1.0; Br, 54.5. Found: C. 28.9; 11, 1 0 ; Br, 54.4. I n this preparation the hydrobromic acid must be colorless. I n one experiment in x-hich this precaution wa3 not observed, no XVII was obtained. Rather, an orange substance, m.p. 264"' was isolated. 2-Amino-4,6-dibroniobenzothiazole is reported as melting a t 261" (22). The substance was not investigated further. 6-Bromo-d-hydrozybenzothiazole. 2,6-Dibromobenzothiazole (10.0 g. , 0.034 mole) was boiled under reflux for 2.5 hours with 250 ml. of 5% sodium hydroxide solution. The cooled filtered solution was acidified with 10% nitric acid and a precipitate of 3.3 g. (46y0)of crude product, m.p. 223-227", separated. Recrystallization from benzene gave fine needles, m.p. 226-228". The reported m.p. for 6-bromo-2-hydrox~benzothiazole prepared by bromination of 2-hydroxybenzothiazole is 226" (44). Nitration of d,G-dzbro~nobel~zofhiazole.2,6-Dibrorno-7-nitrobenzo1hiazole (XVIII). To 20 ml. of conc'd sulfuric acid, 7.85 g. (0.02SS mole) of 2,6-dibromobenzothiazole was slowly added with stirring a t 15-20'. Finely ground potassium nitrate (3.0 g.) (28) was then added t o the mixture over 30 min. during a h i c h lime the temperature waE kept below 40" by intermittent cooling. The mixture was stirred a t room temperature for 1.5 hours, poured into 200 ml. of ice and water, and diluted t o 500 ml. The crude product (9.0 g , m.p. 123-127") was washed with water until the filtrate was neutral t o Congo Red and dried. Slow crystallization froin 95% ethanol gave 6.4 g. (71%) of X V I I I as y ~ l l o ~needles, v m.p. 141-143'. Several further recrystallizations gave an analytical sample, m.p. 142-143'. Bnal. Calc'd for CJLBrJS2Od3: C, 24.9; H, 0.6; Br, 47.3; 9, 8.3. Found: C, 24.9; H, 0.7; N,8.3. Concentration of the alcoholic mother liquor from the first recrystallization of X V I I l to 70 ml. gave 2.1 g. of a mixture, m.p. 123-140". Recrystallization of this from methanol v-ith removal of a small amount of insoluble material gave an isomeric mononitro compound a5 light orange needles, m.p. 125-126" in very low yield. Anal. Found: C, 25.1; H, 0.8; Br, 47.4; N. 8.4. Repeated recrystallization of the above methanol-insoluble material from ethanol gave a third isomer as orange plates, m.p. 176-178". Anal. Found: C , 24.9; E, 0.7; Br, 47.5; X , 8.5. Since the major product (XVIII, m.p. 142-143") apparcntly is the 7-nitro derivative, the two minor products are 2,6-dibromo-4-nitro- and 2,6-dibromo-5-nitro-benzot~iiazole. 6-Brom~-d-methoxy-7-nitrobenzothiazole (XIX) and 6-bromo-2-hydroxy-Y-nitrobenzothiazole (XX) . Because of the insolubility of X V I I I in methanol the procedure used for the preparation of XI11 was nor applicable. The following method (45) was successful. To a

SYNTHESIS OF CERTAIN BEXZOTHIAZOLES

1101

solution of 7.10 g. (0.309 mole) of sodium in 1 1. of dry methanol was added 100 ml. of pyridine (freshly distilled from barium oxide) and 101.5 g. (0.309 mole) of XVIII. After heating t o boiling under reflux a n additional 250 ml. of pyridine was added. rlfter boiling for 2 hours t h e cooled, dark red solution was poured into 3.5 1. of water and diluted t o 6.5 1. The brown flocculent precipitate was collected, washed v,ith water, dried, and extracted in portions with a total of about 2 1. of boiling metlianol. After treating the extract with decolorizing carbon, concentration and refrigeration gave 30.5 g. (34.2%) of X I S as tiny golden needles, m.p. 123-125". Two further recrystallizations from methanol gavc fine yellovl needles, m.p. 128-128.5". A n a l . Calc'd for C&BrS208S. C, 33.2; H, 1.7; Br, 27.6; S ,9.7. Found: C , 33.5; 13, 1.6; Br, 27.4; P;,9.6. An acidic product was isolated by acidification of the aqueous mother liquor from a smaller run in which the pyridine had not been freshly dried. Recrystallization of this from ethanol gave X X as golden needles, m.p. 283" (dec.). Anal. Calc'd for CTH8BrS2O3S:C, 30.6; W, 1.1 ; Br,29.0; S , 10.2. Found: C, 30.7; H, 1.3; Br. 29.1; X , 10.3. For comparison X X was prepared by hydrolysis of XT'III with 5% sodium hydroxide solution as described for the preparation of 6-bromo-2-h~-droxybenzothiazole,The n1.p and mixture m.p. was 280" (dec.). 7-$mzno-8-bromo-~-rnethozlJbelzaolhzazoZe(XXI) . h solution of 2.0 g. (0.0069 mole) of 6-bromo-2-methoxy-7-nitrobenzothiazole in 100 ml. of 95% ethanol i ~ a shaken s a t 40 p,s.i.g hydrogen pressure with 2 g. of palladium on calcium carbonate (35) for 22 hours. The filtered solution on evaporation t o dryness under reduced pressure gave 1.8 g. (100%) of XYI as a light yellow solid, m.p. 103" (dec.). Attempted recrystallization from methanol or ethanol gave a black t a r but the substance separated from hexane (decolorizing carbon) as fine white needles, m.p. 125-127'. $nul. Calc'd for CsHTBrS20S: C, 37.1; H, 2.7; Br, 30.8; S , 10.8. Found: C, 37.4; H, 2.9; Br, 30.6; pu', 10.7. 7 - A m i n o - a - m e t h o z y b e n ~ o ~ ~ ~ a(XXII). zo/e A solution of 2.0 g. (0.0069 mole) of X I S in 100 ml. of methanol containing 2 0 g. (0.024 mole) of anhydrous sodium acetate (46) ',vas shaken as above with 2.0 g. of palladium on calcium carbonate. After 4.5 hours an additional 2.0 g of catalyst was added. After 72 hours the filtered, colorless solution was concentrated nearly t o dryness under reduced pressure and diluted q i t h water. The white solid was collected giving 0.75 g. (60%) of crude X X I I . Recrystallization from petroleum ether (3060") gave white rods, m.p. 73-75'. Anal. Calc'd for CsHsXsOS. C, 53.3; H,4.6; IT.15.5. Found: C, 53.7; H, 4.5;N, 15.4. Reductions in which only an equimolar amount of sodium acetate was present and no fresh catalyst was added after the initial rapid reduction of the nitro group gave mixtures of X X I and X X I I . These mixtures could be separated by recrystallization from aqueous ethanol in which X X I is the less soluble. 7 - C h l o ? o - b - h y d i . o z y b e n ~ o t ~ ~ ~(XXIII). a~ole T o a suspension of 0.5 g. (0.0028 mole) of 7amino-2-methoxybenzothiazole in 6 ml. of conc'd hydrochloric acid and 3 ml of water cooled t o belon- 0" was added dropvise with stirring a solution of 0.21 g. (0.0029 mole) of sodium nitrite i n 1 ml. of water. After a few minutes the clear orange diazonium salt solution was poured slowly into a cold solution of 0.5 g. (0.005 mole) of cuprous chloride in 5 ml. of conc'd hydrochloric acid. After warming the mixture t o 40" until gas evolution ceased and cooling, the yellow solid (0.40 g., 78%) was collected. The crude product as dissolved i n 20 nil. of cold 5% sodium hydroxide solution, and the solution was filtered and acidified with 10% nitric acid. The precipitate was recrystallized twice from benzene (carbon) to give pure X X I I I , m.p. 203-205". Aiaal. Calc'd for C,HdClNOS: C, 45.3; H, 2.2; C1, 19.1; K,7.5. Found: C, 45.2; H, 2.1; C1, 19.4; K,7.4. 4-Chloro-Z-hydrozybenzothiazole (XXIV). 2-Bromo-4-chlorobenzothiazole (0.30 g., 0.0012

I102

R. 6 . ELDERFIELD -4NU F. 'w. SHQBT

mole', w i b h(~il?dunder renus with 15 ml. of 6% sodiuin hydroxide Rolution for 1.5 hours. The produrt was igoltitocl as described a h r e for 6-I~ro~no-2-hydroxyben~otliiazo~e. Kwrysrallixation of the crude suhfii(:ince (0.17 g., 77%), m.p. 2.00-201", from benzene gave iixie nhite needles. n1.p. 2Q2-203". The reported m p . for SXIV prepaied by another ~ncthoct (47) is 204-295". dnc;l. Found: C, 4 5 . 7 ; 13,2.44; C1, 18.9; N, 7.3. A mi\ture of Y X I l I a i d XSSV melted at 163-167".

s~

n

m

4

~

~

1. 2-Amino-4-nitroberizothiazole has been found to be extremely resistant to diazotization. 2. Methyl o-nitrophenylthioncarbammate has been prepared and found to rearrange to methyl o-iiitrophenylthiolcarbamate in the presence of bromine in acetic acid or chloroform. 3. Weakly basic 2-aminobenzothiasoles have been converted to 2-bromobenxothiazoles by Craig's diazotization procedure. 4. 4-Chloro-2-methoxybenzotliiazole reacts with 3-diethylaminopropylamine by displacement of the methoxyl group rather than of the chlorine. 5. Sitratioii of 2 6-dibromobenzothiasole gives as the niajor product a mononitro derivative which is assigned the structure of 2,6-dibromo-7-nitrobenhothiazole dong with small amounts of the 4-arid &nitro isomers. )

NEV YORK27, N. Y.

REFERESCSS (1) Private coinniriniration from Dr. Albert Sabin, The Children's Hospital, Cjncinnati, Ohio. (2) ELUERFIELIJ AND SHORT, unpublished work. (3) Private communication from Dr. L. H. Schmidi, The Christ Hospital Institute for Research, Cincinnati, Ohio. (4) ELDERFIELD AYD S l l O R r , J. olg. CheI/Z., 17, 768 (1953). (5) Drso?; A W GEORGE,,T. Chein. Soc., 126, 1702 (13%). (6) DYSOV, f. Cke??~.S O C . ,174 (1984). (7a) DYBOX, IIUmrER, m i ) ~ ~ I ~ R J. I Y Chem. , Soc., 1186 (1927); (b) E R L E ~ Y E YAXD ER VEBERWASSBR, Hslv. Chim. A c t u . , 23, 328 (1940). (8) D r s o ~ J, . SOC. C'hein. I d , (London) 46, 831' (1929). (9) Thoenov, J. G m . Chein. (Lr. S . S.E . ) , 7, 1688 (1937) [Chern. dbstr., 32, 160 (leJ8)J; IiACFXL4XN A \ l ) SCHIJLZ, r i r c h . PhCLrm., 273, 31 (1335) ; ~ ~ A O N E R - J A I J R E G O AT11 HELMERT, N c r . , 76,935 (1942). (10) S-rrirmvrsx, J . Anz. Chem. Soc., 71, 3117 (1949); KIRK, JOHNSON AND XLONQUIST, J . O r g . Chert?.,8,657 (1943); DROZDOV ANI) STAVHOVSKAY.4, J . Gen. Chem. ( l - . 5. S. E , ) , 7, 2813 (1037) [Chenz. Abslr.) 32, 2943 (1938)j; FAROOQ AXD ~II-?;TER, J. I n d i a , ~Ckem. Soc., 10, 405) 663 (1933) ; EREEYMETCR AKD T~EBERWASSER, Hete. Ckim. Acta., 26, 815 (1942). (11) D ~ V I UAXD S Biox~o~ , I ,, ('hem. Soc., 304 (1942); HVNTER,et nl., J . Chem. Soc., 125, 941 (1930) ; 1755 (1935) i n t e r alia. (12) &II%TmOAND ~'ATANhXE,J . PhUrVl. +%C. JCJ,pcL72, 70, 510 (19%); [CkeVL. RbSf?'.,45, 7111 (1951)]. (13) JAIXBSB:?; M U KLEIN, Rer., 26, 2369 (1893). (14) WORRhLL AND ~ D H I L L l l ' B , J. -47tt. [email protected]., 82, 424 (1%0); \VORH4LL, J. 1\72, Ch4tlL. sOC.,61, 2969 (1939).

SYhTHESIS OF CEETAIK BENZOTHIAZOLES

SI03

(15) WILL, Be?., 16, 339 (lSS2). (16) WHEELERAXD BARSES, Ani. Chern. J . , 24, 71 (1900); 22, 141 (lS99j. (17) SCH~NBERG, et al., Bet .,63, 178 (1930) ; Ann., 483,107 (1930) ; KAI~JAI.A AND MCELVAI~, J . Ant. Chern. Soe., 66, 2966 (1933). (18) VO~OZHTZOV MVD ~JITZENCESDLI:B, J . Gen. Chcm. ( C . S . S . 6, 663, 681 (1936) tCh.m. Abstr., 30, 4862, 6373 (1936,~I. (19) R n a , el al., J . Phalm. Soc. J a p a n , 60, 462 (1940) [Chern. n b s t r . , 35, 453 (194111; DALGLEISH A N D X M S , J . Cliem. Soc., 893 (1945). (20) CRAIG, 3. A m . Chem. Soc., 66, 232 (1934); 68, 2574 (1946); Ar,r.aw AIGD THIX'TLE, 0t.g. Syntheses, 26, 16 (1946). (21) €'GLI,-VZ,N ASD ~ I E T Z G SBull. R , soc. c k i m . Prance, 1021 (1918). (22) C ' K A r D n r , DESAI,ASD IILXTER,J . I n d i a n Chem. Sac., 11, 249 (193t); CHOWDIJVRY A N D HUNTER, Xec. trau. chim., 63, 1 (1934). (23) French Patent 688,867 (1930) [Chein. Abslr.., 26, 96s (lydl)]; British Patent 347,141 (1930) [ChenL. ADstr., 26, 2749 (193211. (24) I'Y;ncoLAs, et al., B i d . soc. ckim. France, 103 (1949). (2s) T r s r r I z A W A , J . Pharrn. SOC.Japan, 62,47 (19-22) [Chem. AAbsir.,46,600 (19Sl)l; OcMAr, et al., J . Pharm. Soc. J a p a n , 63, 258 (1943) [C'hem. Bbstt ., 46, 5153 (1951)l. L?TAXD COCKER, J . Cheni. Soc., 356 (1949). (27) TAXAHASHI AND TANIYAMA, J . Pharm. SOC.J a p a n , 66, 2.1 (1'346) [Chem. Abstr., 46, 8632 (195l)l. (28) KATZ,J . A m . Chem. SOC.,73, 6007 (1951). (29) KIPR~ANOV . ~ S D CYCHE~XO, J . Gen. Cheni. (C-. 8. 8. If.),18, 2U7 ( i 0 6 J [ckerrc.ilbstr., 40,2309 (1946)]. (30) DYROI', HUNTER, JONES, AND S T Y L BJ~. ,Indian Cham. Soc., 8, 147 (1931) (31) HUNTER AiVD P.4RKEN, J . CheVL. SX.,1765 (19%). (32) FRIES AND B U C K L B Ann., ~ , 464, 121 (1927). (33) Fox AND BOGERT, J . Ant. ChenL. Soc., 61, 2013 (1938) (34) ~~HLTJBDBI',ilnn., 668, 10 (1917). (35) Bvsm x~71fhrovx, Ber ., 49, 1063 (1916). (36) British Patents 598,985; 598,986 (1918). (37) I~OOGARTII, J . Chemz. Soc., 3311 (1949). (38) 1 - 1 u > w R , J. Chena. Sue., 128 (1930). (39) ARVDT,Ber., 46, 3328 (1918). (400) SCHIFF AND G N F X b i , Ber., 9, 1316 (1876). (11) K r i z z s ~ Org. , Sy (42) DALGLEISH 4YD & (43) WOOD,Ory. Reactions, 3, 256 (1946). (44) COEOKNA, Pubbl. i n s f . chini. unio. Bologna, Bo. 2-7, 3 (1943) [Chem. Abslr., 41, 754 (1947)l. (451 ELDERFIELD .4SD ICRUCCER, J . 01.g. Chem., 17, 358 (1952). (46) HEAD,U. S. Patent 2,560,960 [Chenz. Abstr., 46, 10443 (1952)l. (47) French Patent 779,282 [Chem. Abstr., 29, 4774 (1935)l; German Patent 615,131 [Chem. Abstr., 29, 6250 (1935)l.